The present invention relates to methods and pharmaceutical compositions for treating and/or preventing inflammatory bowel disease (IBD) and, more particularly, to the use of probiotics for treating and/or preventing IBD, such as Crohn's disease and IBD-related symptoms such as abdominal pain and cramping, diarrhea, rectal and/or intestinal bleeding, weight loss and fever.
Inflammatory bowel disease, or IBD, is a collective term encompassing related, but distinct, chronic inflammatory disorders of the gastrointestinal tract, such as Crohn's disease, ulcerative colitis (UC), indeterminate colitis, microscopic colitis and collagenous colitis, with Crohn's disease and ulcerative colitis being the most common diseases. Ulcerative colitis is confined to the large intestine (colon) and rectum, and involves only the inner lining of the intestinal wall. Crohn's disease may affect any section of the gastrointestinal tract (e.g., mouth, esophagus, stomach, small intestine, large intestine, rectum and anus) and may involve all layers of the intestinal wall. Both diseases, as well as other IBD, are characterized by abdominal pain and cramping, diarrhea, rectal and/or intestinal bleeding, weight loss and fever. The symptoms of these diseases are usually progressive, and sufferers typically experience periods of remission followed by severe flare-ups. Less frequent, but also possible, IBD symptoms reflect mucosal inflammation of other sections of the GI tract, such as duodenitis, jejunitis and proctitis.
A detailed description of IBD symptoms is found in, for example, Northfield, Drugs, Vol. 14, pages 198-206 (1977); Blaker et al, Eur. J. Pediatr., Vol. 139, pages 162-164 (1982); Singleton, The Gastroenterology Annual, pages 268-310 (1983); Saco et al, J. Amer. Acad. Dermatol., Vol. 4, pages 619-629 (1981); Prantera et al, Ital. J. Gastroenterol., Vol. 13, pages 24-27 (1981); Sales et al, Arch. Int. Med., Vol. 143, pages 294-299 (1983); and Ament, Inflammatory Bowel Diseases, Martinus Nijhoff Publ., Boston, Mass., pages 254-268 (1982).
For most patients, IBD is a chronic condition with symptoms lasting for months to years. It is most common in young adults, but can occur at any age. It is found worldwide, but it is most common in industrialized countries such as the United States, England, and northern Europe. In fact, IBD affects an estimated two million people in the United States alone. Although IBD is not considered a fatal illness, prolonged disease can lead to severe malnutrition affecting growth or to the formation of abscesses or intestinal scar tissue, leading in turn to infection or bowel obstruction. Protracted IBD is also known as a risk factor for colon cancer.
Diagnosis of IBD is based on the clinical symptoms, the use of a barium enema, and/or direct visualization (sigmoidoscopy or colonoscopy), with the latter being the most accurate test. For the diagnosis of Crohn's disease, see U.S. Pat. Nos. 6,348,452 and 6,297,015.
The exact causes of IBD are not yet understood. Common hypotheses include, for example, disorders in the immune system and actions of pro-inflammatory cytolines and selective activation of lymphocyte subsets, which perpetuate unrestrained activation of an inflammatory response in the intestine.
IBD has no cure. Patients afflicted with IBD are generally treated currently with therapies that are directed at reducing the inflammatory processes, and at reducing the effects of the inflammatory processes on the patients. The presently known medical treatment of IBD is intended to decrease the number, frequency and severity of acute exacerbations of inflammatory bowel disease and to preventing secondary complications, but at best, the results are disappointing.
The presently known methods for treating IBD have involved anti-inflammatory drugs, immunosuppressive drugs and surgery.
The most commonly used medications to treat IBD are anti-inflammatory drugs such as the salicylates. Preparations of salicylate are effective in treating mild to moderate disease and can also decrease the frequency of disease flares when the medications are taken on a prolonged basis. Examples of salicylates include sulfasalazine, olsalazine, and mesalamine. Particularly, sulfasalazine and related drugs having the bioactive 5-amino-salicylic acid (5-ASA) moiety are widely used to control moderate IBD symptoms and to maintain remission. All of these medications are given orally in high doses for maximal therapeutic benefit. However, treatments with these medications is typically accompanied with adverse side effects such as nausea, dizziness, changes in blood chemistry (including anemia and leukopenia), skin rashes and drug dependence.
Corticosteroids are more potent and faster-acting anti-inflammatory drugs in the treatment of IBD, as compared with salicylates. Prednisone, for example, is a corticosteroid commonly used in the treatment of severe cases of IBD. Nevertheless, potentially serious side effects limit the use of corticosteroids to patients with more severe disease. Side effects of corticosteroids usually occur upon long term use and include thinning of the bone and skin, infections, diabetes, muscle wasting, rounding of faces, psychiatric disturbances, and, on rare occasions, destruction of hip joints.
In cases where IBD patients do not respond to salicylates or corticosteroids, medications that suppress the immune system, namely immunosupprpressants, are used. Examples of immunosuppressants include azathioprine and 6-mercaptopurine. However, as immunosuppressants may render the patient immuno-compromised and susceptible to other diseases, the use thereof in the treatment of IBD is not recommended.
In more severe cases or when the drug therapy fails to relieve the symptoms of IBD, surgical procedures are used. Typical surgical procedures include colectomy, proctocolectomy and ileostomy (See, Cecil Textbook of Medicine, 19th Edition, Wyngaarden et al, ed., 1992). These surgical treatments are radical procedures that often profoundly alter the everyday life of the patient.
In addition to the presently common methods of treating IBD described above, other methods of treating gastrointestinal disorders are disclosed in U.S. Pat. No. 5,110,795 (Hahn), U.S. Pat. No. 5,112,856 (Gaginella et al), U.S. Pat. No. 5,216,002 (Gidda et al), U.S. Pat. No. 5,238,931 (Yoshikawa et al), U.S. Pat. No. 5,292,771 (Backstrom et al), U.S. Pat. No. 5,312,818 (Rubin et al), U.S. Pat. No. 5,324,738 (Dinan et al), U.S. Pat. No. 5,331,013 (Ahlman et al), U.S. Pat. No. 5,340,801 (Ewing et al), U.S. Pat. No. 5,368,854 (Rennick), U.S. Pat. No. 5,391,555 (Marshall et al), U.S. Pat. No. 5,552,439 (Panetta), U.S. Pat. No. 5,569,680 (Wu), U.S. Pat. No. 5,599,795 (McCann et al), U.S. Pat. No. 5,604,231 (Smith et al), U.S. Pat. No. 5,691,343 (Sandborn) and U.S. Pat. No. 5,693,645 (Sharpe et al).
The presently known methods for treating IBD fail to provide a solution for IBD sufferers as these methods (i) fail to provide a substantial cure for IBD, but rather provide treatment of the symptoms; and (ii) include either drug therapy that is accompanied by severe adverse side effects or invasive surgical treatments, both affecting the sufferer's quality of life.
There is thus a widely recognized need for new methods of treating IBD, that would include therapies that are safe, effective, side effect-free and non-invasive.
The present inventors have addressed this issue by providing methods and compositions for treating IBD, which are not based on treating the symptoms but rather address one of the basic causes for IBD, namely, the bacterial equilibrium (balance) in the gastrointestinal (GI) tract. More specifically, the present inventors have envisioned that treating IBD using probiotic formulations would result in alteration of the bacterial balance in the GI tract and would thereby substantially ameliorate or cure IBD.
Probiotics are a class of microorganisms defined as live microbial organisms that beneficially affect the animal and human hosts. The beneficial effects include improvement of the microbial balance of the intestinal microflora or improving the properties of the indigenous microflora. The beneficial effects of probiotics may be mediated by a direct antagonistic effect against specific groups of organisms, resulting in a decrease in numbers, by an effect on their metabolism or by stimulation of immunity. Probiotics may suppress viable counts of an undesired organism by producing antibacterial compounds, by competing for nutrients or for adhesion sites. Further, they may alter microbial metabolism by increasing or decreasing enzyme activity or they may stimulate the immune system by increasing antibody levels or increasing macrophage activity.
It is well known in the art that under conditions where the balance of the GI microflora is adversely affected, probiotics become of potential value in restoring the GI microflora and enabling the individual host to return to normal. Treatments of various GI disorders using probiotic compositions are disclosed, for example, in WO95/16461 and in WO 97/35596.
U.S. Patent Application Publication No. 20020006432 to Collins et al. teach a strain of Bifidobacterium isolated from resected and washed human gastrointestinal tract which is said to be significantly immunomodulatory following oral consumption in humans. The strain is taught to be useful in the prophylaxis and/or treatment of undesirable inflammatory activity, especially gastrointestinal inflammatory activity such as inflammatory bowel disease or irritable bowel syndrome.
Recently, it was uncovered that a single species of a non-pathogenic probiotic microorganism derived from E. coli is, alone, capable of restoring normal GI flora of man and of a variety of mammals and avians. The beneficial physiological and therapeutic activity of this species in the GI tract is described in detail in U.S. patent application Ser. No. 09/725,846 and in PCT/IL01/01088, which are incorporated by reference as if fully set forth herein. These references teach that the Escherichia coli strain BU-230-98 ATCC Deposit No. 202226 (DSM 12799), which is an isolate of the commercially available probiotic E. coli M-17 strain, is highly effective in preventing or treating gastro-enteric infections or disorders, maintaining or reinstating normal gastro-intestinal microflora, preventing or treating diarrhea, preventing or treating gastro-enteric infection caused by an enteric pathogen, such as a Gram negative bacterium or Gram positive bacterium, preventing or treating gastro-enteric Salmonella infection, preventing or treating infectious diarrhea, caused by, for example C. difficile, Salmonella, particularly S. Shigella, Campylobacter, E. coli, Proteus, Pseudomonas or Clostridium or diarrhea resulting from antibiotic therapy, radiotherapy or chemotherapy, and/or for normalizing the physiological activity of the gastrointestinal tract.